Zanidatamab/Chemo Achieves OS Benefit in HER2+ Gastroesopheageal Cancer

Zanidatamab-hrii (Ziihera) plus chemotherapy demonstrated a statistically significant and clinically meaningful improvement in overall survival (OS) compared with trastuzumab (Herceptin) plus chemotherapy as first-line treatment for HER2-positive (HER2+) locally advanced or metastatic gastroesophageal adenocarcinoma (GEA), following its FDA approval in this setting, according to a news release.¹

Second interim OS results from the phase 3 HERIZON-GEA-01 trial (NCT05152147) showed that the OS HR for zanidatamab plus chemotherapy improved compared with the first interim analysis. At the earlier interim analysis supporting zanidatamab’s FDA approval, zanidatamab-hrii plus tislelizumab-jsgr (Tevimbra) and chemotherapy showed progression-free survival and OS benefit, but the zanidatamab/chemotherapy arm had not yet reached statistical significance for OS.²

“These HERIZON-GEA-01 results show that [zanidatamab]-based regimens extend OS, demonstrating definitive superiority of [zanidatamab] over trastuzumab and setting a new benchmark for what a first-line HER2-targeted therapy can achieve,” said Kohei Shitara, MD, director of the Department of Gastrointestinal Oncology and principal trial investigator at the National Cancer Center Hospital East in Kashiwa, Japan, in the news release.¹

Regulatory and Trial Background

The update follows the FDA’s August 25, 2026, approval of zanidatamab, a HER2-directed bispecific antibody, in combination with tislelizumab-jsgr (Tevimbra) and fluoropyrimidine- and platinum-containing chemotherapy for adults with HER2+ (immunohistochemistry [IHC] 3+ and IHC 2+/in situ hybridization [ISH]+) unresectable locally advanced or metastatic GEA, and in combination with chemotherapy alone for patients with HER2+ (IHC 3+) disease.²

HERIZON-GEA-01 is a global, randomized, open-label trial that enrolled 914 patients across approximately 225 sites in more than 30 countries. Patients with unresectable locally advanced, recurrent, or metastatic HER2+ GEA were randomly assigned on a 1:1:1 basis to trastuzumab plus chemotherapy (capecitabine and oxaliplatin [CAPOX] or fluorouracil and platinum [FP]); zanidatamab-hrii plus CAPOX or FP; or zanidatamab-hrii plus tislelizumab-jsgr and CAPOX or FP. The dual primary end points were PFS by blinded independent central review and OS.

At the first interim analysis, the zanidatamab/tislelizumab combination showed a significant PFS benefit over trastuzumab plus chemotherapy with a median PFS of 12.4 months vs 8.1 months, respectively (HR, 0.63; 95% CI, 0.51-0.78; P <.0001), and a median OS of 26.4 months (95% CI, 21.5-30.3) vs 19.2 months (95% CI, 16.8-21.8) with trastuzumab plus chemotherapy (HR, 0.72; 95% CI, 0.57-0.90; P = .0043) The zanidatamab alone arm showed a statistically significant PFS improvement over trastuzumab plus chemotherapy with an HR of 0.65 (95% CI, 0.52-0.81; P < .001) though OS was not statistically significant at that time (HR, 0.80; 95% CI, 0.64-1.01; P = .06); exploratory analyses attributed the effect primarily to patients with HER2 IHC 3+ tumors, among whom median PFS was 14.2 months vs 7.6 months (HR, 0.55; 95% CI, 0.43-0.69).^2,3

Safety Findings

According to the news release, the safety profile of zanidatamab plus chemotherapy with longer follow-up in the second interim analysis was generally consistent with the known safety profiles of the individual agents and with previously reported HERIZON-GEA-01 data, with no new safety signals observed. Diarrhea was the most common grade 3 or higher adverse event, occurring at a rate of 24.8%, 20.0%, and 12.9% in the zanidatamab/tislelizumab, zanidatamab, and trastuzumab arms, respectively.³

REFERENCES

1. Ziihera® (zanidatamab-hrii) plus Chemotherapy Demonstrates Statistically Significant Overall Survival Benefit Versus Trastuzumab plus Chemotherapy in First-Line HER2+ Advanced GEA. News release. Jazz Pharmaceuticals plc. August 31, 2026. Accessed August 31, 2026. https://tinyurl.com/y6frmzds

2. FDA approves zanidatamab-hrii and tislelizumab-jsgr for HER2-positive gastric, gastroesophageal junction, or esophageal adenocarcinoma. News release. FDA. August 25, 2026. Accessed August 25, 2026. https://tinyurl.com/2hceyypc

3. Shitara K, Elimova E, Liu T, et al. Zanidatamab with and without tislelizumab in HER2-positive gastroesophageal cancer. N Engl J Med. 2026;394(20):2002-2014. doi:10.1056/NEJMoa2517729